1. Field of the Invention
The present invention relates to a thioamide compound useful for the synthesis of atorvastatin, a method for producing the thioamide compound, a method for producing a [(4R,6R)-6-aminoethyl-1,3-dioxan-4-yl]acetate derivative using the thioamide compound, and a method for producing atorvastatin using the thioamide compound.
2. Description of the Related Art
Conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) into mevalonate is a rate-determining step in the initial stage of the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit the catalytic action of HMG-CoA reductase on this conversion. In light of this, on the whole, statins are potent lipid lowering substances.
Currently, atorvastatin calcium hydrate is commercially available as Lipitor (R), which has the following formula (see, for example, U.S. Pat. No. 5,273,995).

Atorvastatin calcium is a selective, competitive HMG-CoA inhibitor. In light of this, atorvastatin is a potent lipid lowering substance, and therefore, is useful as a lipid lowering agent and/or cholesterol lowering agent. Further, atorvastatin is also useful for the treatment of osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's disease.
As a method for synthesizing atorvastatin calcium, a synthesis method shown in FIG. 1 is known (see, for example, Roth B. D., et al., Progress in Medicinal Chemistry, 2002, 40, pp. 1 to 22).
However, a problem of the synthesis method shown in FIG. 1 is that this method is not suitable for industrial production since it uses HBr and NaCN and requires an ultra-low temperature step.
In light of the above, various studies have been conducted to search for a novel method for synthesizing atorvastatin.
For example, a method for synthesizing (4R-cis)-1,1-dimethylethyl 6-cyanoethyl-2,2-dimethyl-1,3-dioxane-4-acetate, which is a synthetic intermediate in the method for synthesizing atorvastatin shown in FIG. 1, has been proposed (see, for example, Philip L. Brower, et al., Tetrahedron Letters, Vol. 33, No. 17, pp. 2279 to 2282, 1992).
However, a problem of the technique proposed above is that although (4R-cis)-1,1-dimethylethyl 6-cyanoethyl-2,2-dimethyl-1,3-dioxane-4-acetate is synthesized via a benzenesulfonyl derivative, the benzenesulfonyl derivative does not have sufficient reactivity toward the subsequent step.
Also, a method for synthesizing the (4R-cis)-1,1-dimethylethyl 6-cyanoethyl-2,2-dimethyl-1,3-dioxane-4-acetate by an enzyme method has been proposed (see, for example, International Publication No. WO2004/015132).
The technique proposed above involves a reaction pathway shown in FIG. 2. A problem of this technique is that it requires complicated 3-step enzymatic reactions using three kinds of enzymes, which are ketoreductase (KRED), glucose dehydrogenase (GDH), and halohydrin dehalogenase (HHDH).
Also, as another method, a method for synthesizing tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate, which is an intermediate in the method for synthesizing atorvastatin shown in FIG. 1, has been proposed (see, for example, Stanislav Radl, SYNTHETIC COMMUNICATIONS, Vol. 33, No. 13, pp. 2275 to 2283, 2003).
However, a problem of the technique proposed above is that it requires complicated steps that require oxidation of primary alcohol for introduction of a nitrogen functional group, a nitroaldol reaction, and an elimination reaction for the resulting secondary alcohol.
Accordingly, the current situation is that there is a demand for the provision of a compound enabling the efficient production of a [(4R,6R)-6-aminoethyl-1,3-dioxan-4-yl]acetate derivative using a catalyst that can be prepared at low cost such as a copper catalyst, a method for producing the compound, a method for producing a [(4R,6R)-6-aminoethyl-1,3-dioxan-4-yl]acetate derivative using the compound, and a method for producing atorvastatin using the compound.